Role of CXCR3 Agonists in the Generation of Autoreactive B cells in Scleroderma Patients

Franck Barrat, PhD

Hospital for Special Surgery
Eric Meffre, PhD
Yale University School of Medicine

Project Overview

Dr. Barrat and Dr. Meffre: Scleroderma is a multisystem disorder characterized by vasculopathy, autoimmunity, inflammation, and fibrosis. One of the hallmarks of scleroderma is the presence of autoantibodies and abnormalities of B cell function have been demonstrated in both animal models of scleroderma and in patients. We have shown that an important biomarker of scleroderma, called CXCL4, can inhibit a pathway that is critical for the elimination of B cells that produce these autoantibodies. Now we are investigating how CXCL4 impacts B cell selection and activation.  Furthermore, we are exploring whether it is possible to block CXCL4’s undesirable effect on elimination of autoreactive B cells.

Research Update

Over the past year, we have initiated work on all three parts of this project: delineating the CXCL4 molecular pathway, investigating the activity of CXCL4 in a humanized mouse model, and determining the receptor by which CXCL4 affects elimination of autoreactive B cells. We have identified genes associated with B cell activation that are regulated by CXCL4. We have additionally started to generate the tools required to test the impact of CXCL4 in vivo in humanized mice. Finally, we have completed the third aim of this project in that we have shown that, surprisingly, CXCR3 is not the receptor involved in mediating the effect of CXCL4. These initial findings are exciting, as they provide important insights into how CXCL4 controls B cell activation.

How this work will impact patients

Our ability to characterize the pathways controlled by CXCL4 in B cells in scleroderma patients may identify potential targets for drug development. Other potential benefits would be finding novel biomarkers to help predict disease evolution and select appropriate treatment.

Role of the Scleroderma Research Foundation

This is our first year as members of the SRF’s research group. While both of us are trained immunologists, we greatly value the input of researchers focused on scleroderma. The SRF is an incredible source of knowledge because the best investigators studying scleroderma are part of it. The SRF workshop was very impactful for us; we learned a lot about what others in the field are investigating and how we can incorporate their discoveries into our own research. However, outside the pure academic aspect of this gathering, the general atmosphere both at the scientific sessions and at the more social gatherings is extremely valuable because all of us are dedicated to better understanding this devastating disease and developing new therapeutic strategies for scleroderma patients.

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